The incidence of neuroendocrine tumors is increasing, and the annual prevalence of these malignancies is estimated to exceed 100,000 individuals in the United States. Neuroendocrine tumors are rarely associated with inherited genetic syndromes;however, risk factors for the vast majority of "sporadic" neuroendocrine tumors have not been identified. Similarly, prognostic factors for these tumors are poorly understood. The identification of genetic and molecular prognostic factors for neuroendocrine tumors was identified as a key research priority at a National Cancer Institute summit meeting in September, 2007. Our proposed studies will leverage the resources of a large database of neuroendocrine tumor patients and biospecimens, developed by the PI during his prior K23 career development award. The database provides detailed clinical, pathologic, and outcome data, together with banked germline DNA and archived tumor specimens. Our aims are informed by recent preclinical and clinical data suggesting key roles for angiogenesis and mTOR signaling, as well as by a previous analysis of genomic aberrations in neuroendocrine tumors, performed by the PI. In Aim 1, we propose a two-stage candidate SNP approach to identify and then confirm genetic predictors of risk or survival in these pathways. In Aim 2, we propose to identify and validate immunohistochemical predictors of survival for in these same pathways. In Aim 3, we will assess the potential prognostic significance of chromosome 14q11 amplification or chromosome 18 LOH in small bowel carcinoid tumors. The results will inform our understanding of neuroendocrine tumor risk, prognosis, and biology. Our studies will also potentially identify at-risk populations and new therapeutic targets for this disease. Beyond the proposed aims, this database and specimen repository will allow for the rapid examination of future hypotheses as they emerge. PUBLIC HEALTH RELEVANCE: The diagnosed incidence of neuroendocrine tumors is increasing, yet the genetic and molecular underpinnings of this disease are poorly understood. Our project focuses on identifying genetic and molecular predictors of neuroendocrine tumor risk and prognosis. The results will help identify patients at risk for this disease, identify clinically useful prognostic markers, and identify novel therapeutic targets.